Acid catalyzed aromatic decarboxylation

Electrophilic aromatic substitution is a very important reaction type which has been studied thoroughly. In the more common examples, an aromatic hydrogen atom is substituted by another group. There are other examples in which hydrogen is bonded to the ring and a substituent is 

This section will be concerned with aromatic decarboxylation as an example of an acid catalyzed reaction. The other reactions of this group are discussed in other chapters. 

Benzoic acid and most mono-substituted benzoic acids are stable with respect to decarboxylation in aqueous solution, even at a temperature of 100 °C. However, decarboxylation may occur with a measurable rate if either strong electron-withdrawing or strong electron-releasing substituents are present in the aromatic acid. The decarboxylation rate of 2,4,6-trinitrobenzoic acid is increased by addition of base to the aqueous solution, and it attains a maximum value when the substrate is completely transformed to the anion [236]. A carbon-13 isotope effect of ft, 2/ft, 3 = 1.036 (50 °C) has been observed [237]. There is no D20 solvent isotope effect [238]. These findings indicate that the mechanism of decarboxylation of 2,4,6-trinitrobenzoic acid is a unimolecular electrophilic substitution (SE1), viz. 

Matters are different with aromatic acids carrying electron-releasing substituents as their decarboxylation rates are increased by addition of dilute strong acid. Consequently, another mechanism must be operating. 

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Decarboxylation of histidine to histamine is catalyzed by a broad-specificity aromatic L-amino acid decarboxylase that also catalyzes the decarboxylation of dopa, 5-hy-droxytryptophan, phenylalanine, tyrosine, and tryptophan. a-Methyl amino acids, which inhibit decarboxylase activity, find appfication as antihypertensive agents. Histidine compounds present in the human body include ergothioneine, carnosine, and dietary anserine (Figure 31-2). Urinary levels of 3-methylhistidine are unusually low in patients with Wilson s disease. 

The decarboxylation of carboxylic acid in the presence of a nucleophile is a classical reaction known as the Hunsdiecker reaction. Such reactions can be carried out sometimes in aqueous conditions. Man-ganese(II) acetate catalyzed the reaction of a, 3-unsaturated aromatic carboxylic acids with NBS (1 and 2 equiv) in MeCN/water to afford haloalkenes and a-(dibromomethyl)benzenemethanols, respectively (Eq. 9.15).32 Decarboxylation of free carboxylic acids catalyzed by Pd/C under hydrothermal water (250° C/4 MPa) gave the corresponding hydrocarbons (Eq. 9.16).33 Under the hydrothermal conditions of deuterium oxide, decarbonylative deuteration was observed to give fully deuterated hydrocarbons from carboxylic acids or aldehydes. 

Insertion of aUcynes into aromatic C-H bonds has been achieved by iridium complexes. Shibata and coworkers found that the cationic complex [Ir(COD)2]BF4 catalyzes the hydroarylation of internal alkynes with aryl ketones in the presence of BINAP (24) [111]. The reaction selectively produces ort/to-substituted alkenated-aryl products. Styrene and norbomene were also found to undergo hydroarylation under similar condition. [Cp IrCl2]2 catalyzes aromatization of benzoic acid with two equivalents of internal alkyne to form naphthalene derivatives via decarboxylation in the presence of Ag2C03 as an oxidant (25) [112]. 

We have presented evidence that pyrrole-2-carboxylic acid decarboxylates in acid via the addition of water to the carboxyl group, rather than by direct formation of C02.73 This leads to the formation of the conjugate acid of carbonic acid, C(OH)3+, which rapidly dissociates into protonated water and carbon dioxide (Scheme 9). The pKA for protonation of the a-carbon acid of pyrrole is —3.8.74 Although this mechanism of decarboxylation is more complex than the typical dissociative mechanism generating carbon dioxide, the weak carbanion formed will be a poor nucleophile and will not be subject to internal return. However, this leads to a point of interest, in that an enzyme catalyzes the decarboxylation and carboxylation of pyrrole-2-carboxylic acid and pyrrole respectively.75 In the decarboxylation reaction, unlike the case of 2-ketoacids, the enzyme cannot access the potential catalysis available from preventing the internal return from a highly basic carbanion, which could be the reason that the rates of decarboxylation are more comparable to those in solution. Therefore, the enzyme cannot achieve further acceleration of decarboxylation. In the carboxylation of pyrrole, the absence of a reactive carbanion will also make the reaction more difficult however, in this case it occurs more readily than with other aromatic acid decarboxylases. 

Like the related fatty acid synthases (FASs), polyketide synthases (PKSs) are multifunctional enzymes that catalyze the decarboxylative (Claisen) condensation of simple carboxylic acids, activated as their coenzyme A (CoA) thioesters. While FASs typically use acetyl-CoA as the starter unit and malonyl-CoA as the extender unit, PKSs often employ acetyl- or propionyl-CoA to initiate biosynthesis, and malonyl-, methylmalonyl-, and occasionally ethylmalonyl-CoA or pro-pylmalonyl-CoA as a source of chain-extension units. After each condensation, FASs catalyze the full reduction of the P-ketothioester to a methylene by way of ketoreduction, dehydration, and enoyl reduction (Fig. 3). In contrast, PKSs shortcut the FAS pathway in one of two ways (Fig. 4). The aromatic PKSs (Fig. 4a) leave the P-keto groups substantially intact to produce aromatic products, while the modular PKSs (Fig. 4b) catalyze a variable extent of reduction to yield the so-called complex polyketides. In the latter case, reduction may not occur, or there may be formation of a P-hydroxy, double-bond, or fully saturated methylene additionally, the outcome may vary between different cycles of chain extension (Fig. 4b). This inherent variability in keto reduction, the greater variety of... 

Finally, the decarboxylation of amino acids catalyzed by several pyridoxal phosphate-dependent enzymes has been shown to proceed by a retention of configuration at the Ca atom144. The stereochemical course of the decarboxylation of 5-hydroxy tryptophan to 5-hydroxytryptamine (serotonin) catalyzed by the pyridoxal phosphate-dependent aromatic L-amino acid decarboxylase (equation 15) exemplifies such studies145. 

The concept of inhibition via p elimination of fluoride ion has now been extended to the irreversible inhibition of a-amino acid decarboxylases. Ornithine decarboxylase (ODC), which catalyzes the decarboxylation of ornithine to putrescine is irreversibly inhibited by a-difluoromethylornithine (IX Fig. 9) (28). In this case, the carbanion formation which precedes P elimination is generated by loss of CO2, and not by proton abstraction (Fig. 9). Similarly, aromatic amino acid decarboxylase is irreversibly inhibited by C-difluoromethyl-3,4-dihydroxyphenylalanine (29) while histidine decarboxylase, ornithine decarboxylase and aromatic amino acid decarboxylase have been inhibited by the corresponding <=d-monof luoromethylanri.no acids, respectively (29). 

Aromatic L-amino acid decarboxylase catalyzes the decarboxylation of l-5-hydroxytryptophan (l-5-HTP) to serotonin (5-HT). In the assay, l-5-HTP was used as the substrate and the formation of 5-HT was measured. 

In the presence of the cofactor pyridoxyl phosphate, Dopa decarboxylase catalyzes the decarboxylation of L-dopa to dopamine. This enzyme has been shown to be the same protein as 5-hydroxytryptophan decarboxylase, and both are referred to by the name aromatic L-amino acid decarboxylase (AADC). 

Some work has been done on the kinetics of decarboxylation of aromatic acids in non-aqueous solutions at high temperatures [233]. Usually, the reactions are much faster in aqueous solutions [239] particularly if they are acid catalyzed. Therefore, emphasis in this article will be on decarboxylation in aqueous solution. A brief review has been published in 1968 [240]. In almost all cases, rates can be conveniently followed with the aid of the UV spectrophotometric method. 

DDC catalyzes the conversion of L-3,4-dihydroxyphenylalanine (l-DOPA) into dopamine (Figure 10), a neurotransmitter found in the nervous system and peripheral tissues of both vertebrates and invertebrates and also in plants where it is implicated in the biosynthesis of benzylisoquinoline alkaloids. " DDC also catalyzes the decarboxylation of tryptophan, phenylalanine, and tyrosine and of 5-hydroxy-L-tryptophan to give 5-hydroxytryptamine (serotonin), and, therefore, is also referred to as aromatic amino acid decarboxylase. Inhibitors of DDC, for example, carbiDOPA and benserazide, are currently used in the treatment of Parkinson s disease to increase the amount of l-DOPA in the brain. 

Schiff base formation between pyridoxal phosphate and amino acids are the basis for most enzymatic transformations of amino acids including transamination, decarboxylation, and racemization. Schiff bases formed between amino acids and pyridoxal phosphate or other heteroaromatic or aromatic aldehydes are, however, not only transformed enzymatically, but can, without enzymatic catalysis, undergo a large number of reactions, although at lower rate and/or higher temperatures than those for the corresponding enzymatic reactions. The enzymatic reactions require metal ions as cofactors and in analogy the nonenzymatic reaction are also catalyzed by metal ions, most effectively by cupric ions. 

Dopamine is a key intermediate in the plant BIA biosynthesis pathway. It condenses with 4-HPAA, and forms a BIA scaffold. In plants, tyrosine/ DOPA decarboxylases catalyze the decarboxylation of L-tyrosine and l-DOPA to tyramine and dopamine, respectively [49]. T3Tamine is an undesirable product for bacterial BIA synthetic pathways because its MAO product (i.e., 4-HPAA) combines with dopamine to form norcoclaurine, which needs CYP80B to be converted to reticuline. l-DOPA decarboxylase (PpDODC) from the Pseudomonas putida strain KT2440 exhibited a more than 10 -fold preference for l-DOPA compared with other aromatic amino acids [unpublished data]. Therefore, conversion of l-DOPA with PpDODC is expected to reduce the formation of undesirable by-products, 4-HPAA, and the resultant norcoclaurine (Fig. 1.4). Using an L-DOPA-produdng E. coli strain that overexpresses PpDODC, dopamine production reached 1.05 g. The conversion efficiency from L-tyrosine to dopamine was 29.1 % [24]. 

Decarboxylation reactions are also a common type of elimination in NCW. Both aliphatic and aromatic carboxylic acids will undergo elimination of CO2 in NCW. Since decarboxylations produce CO2, the resulting carbonic acid can have an accelerating effect on numerous acid-catalyzed processes. Carlsson et al. studied the conversion of citric and itaconic acids to methacrylic acid, suggesting decarboxylation of acotinic acid yielding methacrylic acid (Fig. 9.32). The authors reported NMR evidence that supports... 

Decarboxylation. Decarboxylation of linear and aromatic carboxyUc acids and of amino acids is common and of practical interest. L-Lysine [56-87-1] (48) can be synthesized by stereospecific decarboxylation of meso- (but not DL-) aa -diaminopimehc acid [2577-62-0] (49). The reaction is catalyzed by Bacillus sphaericus and proceeds in quantitative yields (92). 

The usual sources used for the homolytic aromatic arylation have been utilized also in the heterocyclic series. They are essentially azo- and diazocompounds, aroyl peroxides, and sometimes pyrolysis and photolysis of a variety of aryl derivatives. Most of these radical sources have been described in the previous review concerning this subject, and in other reviews concerning the general aspects of homolytic aromatic arylation. A new source of aryl radicals is the silver-catalyzed decarboxylation of carboxylic acids by peroxydisulfate, which allows to work in aqueous solution of protonated heteroaromatic bases, as for the alkyl radicals. 

The thermal decomposition of MCPBA is slow and unselective. When cobalt catalyzed, the initial reaction is very fast and selective but the reaction is Wdered by the re-arrangement of Co(in)a to Co(III)s and by the slow reaction with m-chlorotoluene. These reactions are also characterized by a high steady state concentration of Co(III). High concentrations of Co(III) are not desirable because Co(III) is known to react with the acetic acid solvent and also decarboxylate aromatic acids (2). 

The potential of benzoylformate decarboxylase (BFD, E.C. 4.1.1.7) to catalyze C-C bond formation was first reported by Wilcocks at al. using crude extracts of Pseudomonas putidsL [50]. They observed the formation of (S)-2-hydroxy-l-phenylpro-panone (S)-2-HPP when benzoyl formate was decarboxylated in the presence of acetaldehyde. Advantageously, aldehydes - without a previous decarboxylation step - can be used instead of the corresponding more expensive a-keto acids [51]. We could show that BFD is able to bind a broad range of different aromatic, heteroaromatic, and even cyclic aliphatic and conjugated olefinic aldehydes to ThDP before ligation to acetaldehyde or other aldehydes (Table 2.2.7.3) [52]. 

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